: The mechanisms allowing women with estrogen dependent breast cancer to respond to secondary hormonal therapies are incompletely understood. As a potential explanation, the applicant postulated that breast cancer cells adapt to estrogen deprivation by developing hypersensitivity and developed a model system demonstrating this phenomenon. Based on the results, the applicant suggested that hypersensitivity is not mediated primarily at the level of estrogen receptor transcription but rather involves up-regulation of growth factor signaling pathways. His working hypothesis is that growth factor and estrogen mediated events interact synergistically at the level of the cell cycle to mediate hypersensitivity. The proposed studies will further examine growth factor pathway up-regulation and determine the specific mediators responsible. Based upon recent preliminary data, the applicant will also examine hypersensitivity and apoptosis. In his model, long term estrogen deprivation sensitizes cells to a paradoxic, stimulatory effect of estradiol on apoptosis. Accordingly, he plans to systematically examine this phenomenon and has envisioned a novel breast cancer treatment based upon his findings. The strategy rests upon the concept that cell proliferation and apoptosis are intrinsically linked and regulated by survival factors. Certain proteins such as c-Myc, activated Ras, MAP kinase, and E2F1 and that a PI-3-kinase inhibitor can induce apoptosis. The integration of these concepts provides a rationale to "Kill" tumor cells with estrogen as part of a combined treatment strategy for breast cancer. This utilizes alternate cycles of therapy first to block cell proliferation with anti-estrogens and growth factor inhibitors and then to stimulate apoptosis with estradiol and PI-3-kinase inhibitors. Specific Aim 1 will demonstrate which growth factor mediated pathways are up regulated during adaptation to long term estradiol deprivation. Specific Aim 2 will delineate the separate mechanistic roles of c-Myc and the MAP kinase pathway on cell proliferation and on cell death. Specific Aim 3 will optimize the conditions for enhancing apoptosis and inhibiting cell proliferation in vitro. Specific aim 4 will demonstrate in an in vivo model that the strategy of alternate blockade of proliferation followed by stimulation of apoptosis results in greater tumor regression than with each intervention alone. The applicant expects these studies to be the basis for future clinical trials.